rs121912562

Variant names:

• chr4-148435252-G-A
• rs121912562
• NM_000901.5:c.1609C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-148435252-G-A
• chr4-148435252-G-C
• chr4-148435252-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000901.5(NR3C2):​c.1609C>T​(p.Arg537*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR3C2 NM_000901.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.19
• Publications: 5 publications found

Genes affected

NR3C2 (HGNC:7979): (nuclear receptor subfamily 3 group C member 2) This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NR3C2 Gene-Disease associations (from GenCC):

• autosomal dominant pseudohypoaldosteronism type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohyperaldosteronism type 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-148435252-G-A is Pathogenic according to our data. Variant chr4-148435252-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8555.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000901.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.1609C>T	p.Arg537*	stop_gained	Exon 2 of 9	NP_000892.2
	NR3C2	NM_001437657.1		c.1609C>T	p.Arg537*	stop_gained	Exon 2 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.1609C>T	p.Arg537*	stop_gained	Exon 2 of 9	NP_001424583.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.1609C>T	p.Arg537*	stop_gained	Exon 2 of 9	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.1609C>T	p.Arg537*	stop_gained	Exon 2 of 8	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.1609C>T	p.Arg537*	stop_gained	Exon 1 of 8	ENSP00000421481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000126 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autism spectrum disorder (1)
1	-	-	Autosomal dominant pseudohypoaldosteronism type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		5.2
Vest4		0.96
GERP RS		4.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912562; hg19: chr4-149356404; COSMIC: COSV60988288;